RARE DISEASE
Inherited arrhythmogenic cardiomyopathy
Inherited arrhythmogenic cardiomyopathy
Inherited arrhythmogenic cardiomyopathy
Synonyms: Arrhythmogenic right ventricular cardiomyopathy
Synonyms: Arrhythmogenic right ventricular cardiomyopathy
Synonyms: Arrhythmogenic right ventricular cardiomyopathy
Drug discovery
5
drugs
With orphan designations
Overview
Inherited arrhythmogenic cardiomyopathy (ACM) is a genetic disorder characterized by progressive replacement of ventricular myocardium with fibro-fatty tissue, predisposing to life-threatening ventricular arrhythmias and sudden cardiac death. Primarily affecting the right ventricle (ARVC), it can also involve the left (ALVC) or both ventricles. Desmosomal gene mutations (e.g., PKP2, DSG2) are implicated in ~50% of cases, with autosomal dominant inheritance and variable penetrance. Clinical features include palpitations, syncope, and heart failure, often manifesting in adolescence or young adulthood [1][2][6][19].
Burden
Leads to sudden cardiac death in ~2–5% of cases annually, often in young individuals/athletes [1][18].
Economic strain from ICD costs, genetic testing, and lifelong surveillance; psychological impacts on families [9][14].
Progressive heart failure necessitates transplantation in 5–10% of advanced cases [3][13].
Therapies
Risk stratification: Implantable cardioverter-defibrillators (ICDs) for high-risk patients (e.g., survivors of cardiac arrest, severe ventricular dysfunction) [3][17].
Antiarrhythmics: β-blockers (first-line), amiodarone, or flecainide for symptomatic ventricular arrhythmias [3][8][17].
Ablation: Combined endo-/epicardial catheter ablation for recurrent ventricular tachycardia [8][13].
Lifestyle: Strict exercise restriction to mitigate disease progression [2][8][18].
Categories: rare cardiac diseases, rare genetic diseases, rare transplant-related disorders
Research Papers
720 drug discovery papers about Inherited arrhythmogenic cardiomyopathy, with 5 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
720 drug discovery papers about Inherited arrhythmogenic cardiomyopathy, with 5 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-04 | Lipid Metabolism as a Therapeutic Target in Arrhythmogenic Cardiomyopathy: Emerging Therapeutic Implications of Lipid-Lowering Therapy.
Arrhythmogenic cardiomyopathy (ACM) is a hereditary myocardial disorder characterized by progressive replacement of ventricular myocardium with fibro-fatty tissue, leading to life-threatening ventricular arrhythmias and heart failure. Historically, management has focused on arrhythmia suppression and prevention of sudden cardiac death (SCD). However, recent advances in understanding disease mechanisms have redefined ACM as a structural-metabolic cardiomyopathy. Central to this evolving paradigm is the "adipogenic switch", driven by desmosomal dysfunction, impaired Wnt/β-catenin signaling, and activation of the peroxisome proliferator-activated receptor gamma (PPARγ) pathway. Emerging evidence highlights the critical role of metabolic dysregulation, specifically the oxidized low-density lipoprotein (oxLDL)/cluster of differentiation 36 (CD36)/PPARγ axis, in driving disease progression. Elevated oxLDL levels correlate with greater phenotypic severity, increased ventricular fat infiltration, and a higher arrhythmic risk. Translational models demonstrate that high-fat diets exacerbate the ACM phenotype, whereas lipid-lowering interventions, particularly statins, show potential to arrest fibro-fatty remodeling. In addition to the primary inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase associated with statins, these medications exert pleiotropic effects, including attenuation of systemic inflammation, stabilization of the intercalated disc via Rho GTPase modulation, and reduction of oxidative stress. Clinical data from non-ischemic dilated cardiomyopathy (NIDCM) suggest that lipophilic statins such as atorvastatin, may confer significant mortality and antiarrhythmic benefits by stabilizing the myocardial electrical substrate. The ongoing SEARCH trial (NCT06922994) represents a landmark effort to translate these insights into clinical practice. Using high-dose atorvastatin and sensitive primary endpoints, such as right ventricular free wall longitudinal strain, this study aimed to determine whether lipid-lowering therapy can function as a true disease-modifying intervention in ACM. The integration of lipid-lowering agents into the therapeutic armamentarium for ACM could enable a transition toward precision medicine, contingent upon successful clinical validation. If clinical trials confirm the efficacy of these agents in slowing myocardial substrate decay, this approach could redefine the management of ACM, including the use of targeted molecular strategies to preserve myocardial identity and electrical stability.
2026-07-08 | Genotype-Specific Electrophysiological Remodeling in PLN R14del Cardiomyopathy: Implications for Precision Antiarrhythmic Therapy.
Inherited PLN (phospholamban) R14del variants cause dilated cardiomyopathy with a high burden of malignant ventricular arrhythmias. However, the single-cell electrophysiological substrate underlying arrhythmogenicity is incompletely characterized, and it is unclear whether antiarrhythmic agents validated in wild-type (WT) or long QT models retain efficacy in this genotype. We sought to define the genotype-specific electrophysiological phenotype of PLN R14del cardiomyocytes and evaluate how modulation of the transient outward potassium current and late sodium current alters arrhythmic risk. Isogenic WT (HD.15S1) and CRISPR (clustered regularly interspaced short palindromic repeats)-edited PLN R14del human induced pluripotent stem cell-derived cardiomyocytes were studied using high-throughput optical action potential (AP) recordings. A deep learning framework classified AP morphology to quantify normal versus aberrant AP types, AP duration, and early afterdepolarization incidence at baseline and under graded concentrations of the transient outward potassium current activator NS-5806, the transient outward potassium current inhibitor acacetin, and the selective late sodium current blocker GS-967 (eleclazine). At baseline, PLN R14del human induced pluripotent stem cell-derived cardiomyocytes exhibited a subtle but significant arrhythmogenic phenotype, with a reduced proportion of normal APs, prolonged AP duration, and increased early afterdepolarizations compared with isogenic WT, consistent with impaired calcium handling and diminished repolarization reserve. In WT cells, NS-5806 produced a biphasic, dose-dependent response, transiently destabilizing and then restoring normal AP morphology; in PLN R14del cells, NS-5806 induced marked proarrhythmic remodeling and near-complete loss of normal APs at higher doses. GS-967 paradoxically exacerbated arrhythmic features in the mutant line, including AP duration prolongation and suppression of normal APs. Acacetin preserved stability in WT cells but failed to rescue normal AP morphology in PLN R14del cardiomyocytes. PLN R14del cardiomyopathy creates a distinct electrophysiological substrate that fundamentally alters antiarrhythmic drug responsiveness, such that agents beneficial in WT contexts may be ineffective or proarrhythmic in this genotype. Preclinical antiarrhythmic evaluation should incorporate genotype-specific, patient-derived human induced pluripotent stem cell models to enable precision medicine strategies in inherited cardiomyopathies.
2026-06-29 | TGF-β2 signaling promotes cardiac fibrosis in arrhythmogenic right ventricular cardiomyopathy mediated by DSC2 deficiency.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by progressive fibrofatty replacement of the right ventricular myocardium, ventricular arrhythmias, and an increased risk of sudden cardiac death. Pathogenic variants of desmosomal genes have been implicated in ARVC pathogenesis and may disrupt desmosomal protein function. However, whether and how desmosomal protein dysfunction directly activates cardiac fibroblasts to mediate fibrosis remains poorly understood. To address this, we combined genetic analysis with in vivo and cellular models to investigate the role of desmosomal dysfunction in cardiac fibrosis. The systematic genetic analysis revealed that desmosomal gene variants are predominant in ARVC, accounting for 67.4% of cases in cohort studies and 96.1% of pathogenic variants in ClinVar. We used desmocollin-2 (DSC2) knockout mice to recapitulate key features of ARVC, including right ventricular fibrosis, enlargement, and dysfunction. In vitro, DSC2 deficiency directly activates cardiac fibroblasts, resulting in increased cell proliferation, migration, and fibrosis marker expression. Further analysis identified transforming growth factor beta-2 (TGF-β2) as a critical signaling mediator in cardiac fibrosis of DSC2 deficiency-mediated ARVC. Mechanistically, DSC2 deficiency upregulated transcription factor 7 (TCF7) expression, promoting its binding to TGF-β2 promoter regions to enhance TGF-β2 transcription in cardiac fibroblasts. Pharmacological inhibition of TGF-β2 with pirfenidone (PFD) effectively attenuated cardiac fibrosis and improved right ventricular function in DSC2-deficient hearts. The results of the present study identified DSC2 deficiency-mediated TCF7-TGF-β2 signaling in cardiac fibroblasts, which contributed to ARVC development. Thus, targeting TGF-β2 signaling may be a promising therapeutic strategy for desmosome gene mutation-related ARVC.
2026-06-27 | Desmoglein-2 Deficiency Drives Mitochondrial Morphological Remodeling in Cardiomyocytes.
Pathogenic variants in desmoglein-2 (DSG2) are a major cause of arrhythmogenic cardiomyopathy (ACM), a disease plagued by ventricular arrhythmias, contractile dysfunction, myocardial inflammation, and fibrofatty remodeling. Additionally, increasing evidence implicates mitochondrial dysfunction in DSG2-associated disease. However, whether mitochondrial remodeling occurs uniformly across ventricles remains less well defined. Here, we utilized a homozygous Dsg2 mutant (Dsg2mut/mut) mouse to define chamber-specific mitochondrial remodeling in DSG2-linked ACM. Re-analysis of our previously generated cardiomyocyte snRNAseq dataset revealed broad downregulation of mitochondrial transcripts involved in fusion/fission dynamics, calcium handling, mitophagy, structural organization, and electron transport chain (ETC) assembly, findings that are consistent with impaired mitochondrial homeostasis and bioenergetic capacity. Ultrastructural analyses by transmission electron microscopy showed that Dsg2mut/mut hearts contained an increased number of mitochondria, which were smaller, irregularly shaped, and more disorganized than wildtype (WT) counterparts. Importantly, these alterations were chamber-dependent, with the right ventricle (RV) displaying more pronounced reductions in mitochondrial circularity and greater mitochxondrial abundance than the left ventricle (LV), indicating increased RV susceptibility. Together, these findings unveil mitochondrial remodeling as a feature of DSG2-deficiency and support a desmosomal-mitochondrial axis in ACM pathogenesis, further supporting mitochondrial pathways as candidate therapeutic targets.
2026-06-23 | Sacubitril/valsartan in paediatric cardiomyopathy: a retrospective evaluation of ventricular response and clinical outcomes.
Sacubitril/valsartan is widely used in adults with heart failure with reduced ejection fraction, but paediatric experience, especially across ventricular dysfunction phenotypes, remains limited. To evaluate the efficacy and tolerability of sacubitril/valsartan in children with cardiomyopathy and compare outcomes in patients with predominantly right or left ventricular dysfunction. This single-centre retrospective study included 33 patients aged 1 month to 18 years who received sacubitril/valsartan between October 2020 and October 2024. Diagnoses included arrhythmogenic right ventricular cardiomyopathy, left ventricular non-compaction, and dilated cardiomyopathy. Patients were stratified by predominant ventricular dysfunction. Echocardiographic parameters, N-terminal pro B-type natriuretic peptide, six-minute walk test, NYHA class, blood pressure, creatinine, and potassium were recorded at baseline and at 1, 3, and 6 months, and at final follow-up. Clinical outcomes included rehospitalisation, death, and heart transplantation or listing. The cohort included 21 male patients (63.6%), and the median age was 8.6 years. Arrhythmogenic right ventricular cardiomyopathy was present in 45.5%, left ventricular non-compaction in 15.2%, and dilated cardiomyopathy in 39.4%. Left ventricular ejection fraction >45% increased from 39.4% to 72.7%. Mean N-terminal pro B-type natriuretic peptide decreased from 6309 to 3137 pg/mL (p < 0.001). NYHA class improved or remained stable in 93.3% of patients, with greater improvement in left ventricular dysfunction. During a median 17.3-months follow-up, rehospitalisation occurred in 42.4%, and 5 patients died or underwent heart transplantation/listing. Hypotension occurred in 18.2% but was manageable. Sacubitril/valsartan was generally well tolerated and associated with improved ventricular function, biomarkers, and functional status in paediatric cardiomyopathy, particularly in left ventricular dysfunction.
gene therapies
2026-05-11 | Gene Therapy for Cardiomyopathy: Tools, Targets, and Trials.
Cardiomyopathy remains a leading cause of heart failure-related morbidity and mortality, driven by diverse genetic architectures that include monogenic variants, oligogenic interactions, and polygenic risk. Rapid advances in genomic medicine and vector engineering have positioned cardiac gene therapy as a transformative therapeutic approach. Adeno-associated virus-mediated gene replacement for hypertrophic, dilated, and arrhythmogenic cardiomyopathies has transitioned into early-phase clinical trials, with emerging data providing promising signals of myocardial transgene expression and improvements in circulating biomarkers such as NT-proBNP (N-terminal pro-B-type natriuretic peptide). Genome-editing platforms-including CRISPR-mediated base editing and prime editing-offer the potential for durable variant correction without introducing double-stranded breaks. Yet, major translational challenges remain, including strategies to bypass liver uptake to ensure high-efficiency transduction of cardiomyocytes, overcoming delivery constraints, including the cargo size of adeno-associated virus vectors, addressing toxicities, and establishing adequate immunosuppressive regimens. Novel strategies such as direct antegrade and retrograde coronary infusion, capsid engineering, split-intein dual-adeno-associated virus systems, miniaturization of CRISPR-related proteins, and nonviral nanoparticles are underway. As first-in-human cardiomyopathy gene therapy trials begin to define safety, dosing, and vector tropism in the failing human heart, the field is entering an inflection point where genomic diagnosis, molecular correction, and phenotype-guided delivery can converge into precision heart failure therapeutics. This review highlights current progress, emerging platforms, and scientific hurdles that must be overcome to realize a new era of potentially curative, mechanism-directed therapy for inherited and acquired cardiomyopathies.
2026-04-10 | Gene Editing Strategies (CRISPR) for Inherited Cardiomyopathies: Ethical, Technical and Clinical Review
Background: Inherited cardiomyopathies, such as hypertrophic, dilated and arrhythmogenic, are mediated by clearly defined genetic variants that are hard to combat using traditional therapy. Recent developments of gene-editing systems including CRISPRCas systems provide the opportunity to correct the causative mutations however, their translation elicits complicated ethical, technical and clinical issues. Objective: To overview the existing gene-editing options of inherited cardiomyopathies and assess their therapeutic potential, obstacles and available challenges of clinical use. Method: This was a review of preclinical research, initial therapeutic trials, genome-engineering system and bioethical models. It was emphasized on CRISPR-Cas9, base editing and prime-editing methods, as well as delivery methods such as AAV vectors and lipid nanoparticles. Moral considerations were done on the manipulation of germlines, off-target editing and long term consequences to society. Results: In animal and cellular models, gene editing demonstrated good possibilities in correcting pathogenic variants inMYH7, MYBPC3, LMNA and PKP2, and results were observed in improvement of myocardial structure and functioning. But there are still significant technical hurdles such as off-target effects, immune response to Cas proteins and limited efficacy of myocardial delivery. The ethical review pointed out the issues of germline edits, fair access and a long-term safety followup. Conclusion: Gene-editing technologies have a high potential of creating a new therapeutic alternative in inherited cardiomyopathies, considerable ethical, biological and translational challenges need to be overcome before clinical adoption. Additional streamline editing accuracy, delivery platform and regulatory authorities will be required to make them safe and responsible.
2026-04-04 | Adenovirus-associated viral vector-based gene-replacement therapy for the treatment of arrhythmogenic cardiomyopathy: A risk-benefit perspective in an evolving field.
Arrhythmogenic cardiomyopathy (ACM) is a primary disorder of the myocardium characterized by a high propension for ventricular arrhythmias (VAs) and sudden cardiac death (SCD). Several genes have been associated with the development of aggressive forms of ACM, the most common of which is the one encoding for plakophilin-2. Currently, no disease-modifying treatment for ACM exists and current therapeutic options are limited to implantable cardioverter defibrillator (ICD) for SCD prevention. In recent years, the use of adeno-associated viral vector (AAVV)-based gene-replacement therapies for the potential treatment of some ACM forms have been proposed with several technologies and related trials in the development pipeline. The main aim of this review is to highlight the state of current AAVV technologies, to summarize the prior experiences with their use in the field of cardiovascular medicine, and to specifically focus on the currently active trials with AAVV technologies in the field of ACM with a great focus on plakophilin-2 efforts. Side effects associated with AAVV administration, potential caveats associated with immunosuppression and realistic biological and clinical outcomes will be discussed in the review. We hope to provide data and perspective to clinicians to foster education in these novel technologies and to empower providers in their risk/benefit conversations with patients with ACM interested in pursuing them.
2026-02-28 | Fibroblast growth factor 21 prevents catecholaminergic arrhythmias in a mouse model of PKP2 arrhythmogenic cardiomyopathy.
Pathogenic variants in plakophilin-2 (PKP2) cause arrhythmogenic cardiomyopathy (ACM) with intracellular calcium dysregulation as a major component of its arrhythmia phenotype. Recent adeno-associated virus (AAV)-based PKP2 gene therapy has shown promising results in a few different PKP2-associated ACM models. Fibroblast growth factor 21 (FGF21) has multiple cardioprotective effects and has recently emerged as a promising therapeutic agent for cardiovascular disease. This study aimed to assess the efficacy and impact on calcium regulation of a novel AAV serotype 8 (AAV8)-based FGF21 gene therapy on adult cardiac-specific, tamoxifen-activated PKP2 knockout (PKP2-cKO) mice. Experiments were performed using a PKP2-cKO murine model. AAV8-FGF21 was delivered to adult mice by a single tail vein injection 7 days before tamoxifen-activated PKP2-cKO. Cardiac functions were monitored using echocardiography and electrocardiography. Intracellular calcium transients were investigated in acute isolated adult mouse cardiomyocytes, and calcium fluorescent signals were acquired using the IonOptix system. Loss of PKP2 expression caused cardiac mechanical dysfunction and proarrhythmic phenotype in adult mouse models. AAV-mediated delivery of FGF21 mitigated the progression of biventricular structural changes, decreased the occurrence of adrenergic arrhythmias, and rescued intracellular calcium imbalance in the setting of PKP2 haploinsufficiency. In contrast, acute in vitro FGF21 treatment for 1 hour had no effect on intracellular calcium transients. These beneficial effects of AAV8-FGF21 on the PKP2-ACM phenotype suggest a therapeutic landscape for various targeted cardiomyopathies.
2026-01-27 | Genetics of Sudden Cardiac Death.
Cardiomyopathies (DCM, HCM, and ACM) and primary arrhythmogenic disorders (BrS, LQTS, and CPVT) represent the most common causes of sudden cardiac death (SCD) in young individuals. Systematic genome-wide single-nucleotide polymorphism (SNP) analyses and genome-wide association studies (GWASs) have enabled the identification of numerous genetic variants associated with cardiovascular diseases. Body: Genetic testing for cardiomyopathies and inherited channelopathies primarily involves panel testing of genes with definitive and strong evidence of disease association; genes supported by moderate evidence may also be considered. Cardiomyocytes express a variety of proteins implicated in the pathogenesis of genetic cardiomyopathies, including sarcomeric, cytoskeletal, desmosomal, and nuclear envelope proteins. Inherited cardiac channelopathies result from mutations in genes encoding cellular components that influence calcium ion availability or affect membrane ion channels, including sodium, potassium, and calcium channels. Common variants associated with SCD are found in genes encoding cardiac ion channels (e.g., SCN5A, KCNQ1, and KCNH2), calmodulin (CALM2), sarcomeric proteins (MYH7, MYBPC3, TTN, and TNNI3), and desmosomal proteins (RyR2 and DES). This review demonstrates that specific genetic variants are significantly associated with an increased risk of SCD. The evidence underscores the importance of genetic screening and early intervention in individuals with a family history of SCD or other risk factors for inherited cardiac disorders predisposing to SCD. Future research should focus on gene-specific management strategies for familial cardiomyopathies and inherited channelopathies, with the goal of improving targeted genetic therapies and reducing the burden of sudden cardiac death.
cell therapies
2026-01-28 | Generation of a PKP2 heterozygous knockout pig model of arrhythmogenic cardiomyopathy.
Arrhythmogenic cardiomyopathy (ACM) confers elevated risk of ventricular arrhythmias and sudden cardiac death, yet limitations in early lesion sampling and model development continue to hinder mechanistic and translational research. Clinical, pathological, and mutational profiles were examined in 24 individuals with ACM harboring PKP2 variants. Among these, a patient carrying the c.1132C>T mutation exhibited the earliest onset and presented both structural cardiac abnormalities and major adverse cardiovascular events. To facilitate disease modeling, the c.1147C>T variant-a previously reported pathogenic substitution located proximal to position c.1132 in PKP2-was selected to enhance the feasibility of generating a porcine model. The BE3 gene editing system was used to induce C>T mutation. Two single guide RNAs targeting the PKP2 gene were designed (sgRNA1 for c.1132C>T and sgRNA2 for c.1147C>T), yielding editing efficiencies of 42.9% and 25.9%, respectively. SgRNA1 was used to generate PKP2 +/- porcine fetal fibroblasts. A total of 14 cloned piglets were produced, including 11 viable and three stillborn PKP2 +/- individuals. By 24 months of age, PKP2 +/- pigs developed premature ventricular contractions and right ventricular dilatation. Histological analysis revealed adipocyte infiltration within the right ventricular wall, and electron microscopy demonstrated reduced desmosomal length and electron density consistent with desmosomal dysfunction. Transcriptomic profiling showed high expression of genes associated with lipid catabolic processes. This study established the first PKP2 +/- porcine model of ACM using BE3-mediated base editing, providing a valuable platform for elucidating early pathogenic mechanisms and evaluating therapeutic interventions.
2025-11-03 | Cardiac sympathetic denervation for refractory ventricular arrhythmias in patients with inherited cardiomyopathies.
Cardiac sympathetic denervation (CSD) is a therapeutic option in patients with recurrent or refractory ventricular arrhythmia (VA). Successful outcomes have largely been established among patients with underlying ischemic cardiomyopathy, patients with nonischemic cardiomyopathy, and young patients diagnosed as having long-QT syndrome or catecholaminergic polymorphic ventricular tachycardia. Patients with inherited cardiomyopathies have a rare prevalence but experience VAs and sudden cardiac death. Herein, we studied the outcomes of CSD on patients with refractory VA and an inherited cardiomyopathy. Data from adult patients with VA referred for CSD were reviewed from 4 tertiary referral centers between 2010 and 2023. Patients with a minimum postoperative follow-up time of 12 months and an inherited cardiomyopathy were included: hypertrophic cardiomyopathy, arrhythmogenic cardiomyopathy, or dilated cardiomyopathy. 23 patients with an inherited cardiomyopathy underwent bilateral CSD: 7 patients with hypertrophic cardiomyopathy, 11 patients with arrhythmogenic cardiomyopathy, and 5 patients with dilated cardiomyopathy. The median (interquartile range) follow-up time was 34.5 months (23.1-46.5). The overall success rate of CSD was 48%. When comparing pre- and post-CSD periods, implantable cardioverter-defibrillator shocks decreased by 61% (P < .01). Transplant-free survival at 4 years was 76%. Most of the expected complications resolved upon follow-up. Bilateral CSD significantly reduced implantable cardioverter-defibrillator shocks in patients with inherited cardiomyopathies, demonstrating durable arrhythmia control and favorable long-term transplant-free survival across diverse genetic subtypes.
2025-08-26 | The blueprint of neurocardiac crosstalk in arrhythmic syndromes.
Inherited arrhythmogenic syndromes encompass a spectrum of genetic cardiac disorders unified by heightened vulnerability to sympathetic stimulation and risk of sudden cardiac death. Traditionally categorized as either functional (e.g., catecholaminergic polymorphic ventricular tachycardia, CPVT) or structural (e.g., arrhythmogenic cardiomyopathy, ACM), these syndromes are increasingly recognized to share a common reliance on neurocardiac signaling. In this review, we examine CPVT and ACM as representative extremes of the functional-structural continuum, highlighting how sympathetic activation acts not only as an acute arrhythmic trigger but also as a chronic driver of disease progression. We dissect the roles of β-adrenergic signaling, neuropeptide Y (NPY), and regional innervation patterns in shaping myocardial excitability, remodeling, and arrhythmogenesis. While CPVT exemplifies a trigger-dependent, Ca2+-driven arrhythmia in structurally normal hearts, ACM demonstrates a substrate-amplified phenotype involving maladaptive autonomic remodeling and neurogenic fibrofatty infiltration. We discuss the emerging relevance of neuromodulatory and peptidergic therapies-including β-blockade, left cardiac sympathetic denervation, and NPY antagonism-and propose an integrated framework for arrhythmia classification and management based on autonomic mechanisms. By reframing inherited arrhythmias as disorders of integrated neural and myocardial physiology, we highlight new opportunities for mechanistic insight, biomarker development, patient stratification, and translational therapy.
2024-02-23 | Extracellular vesicles from immortalized cardiosphere-derived cells attenuate arrhythmogenic cardiomyopathy in desmoglein-2 mutant mice.
Arrhythmogenic cardiomyopathy (ACM) is characterized by progressive loss of cardiomyocytes, and fibrofatty tissue replacement. Extracellular vesicles (EVs) secreted by cardiosphere-derived cells, immortalized, and engineered to express high levels of β-catenin, exert anti-inflammatory, and anti-fibrotic effects. The aim of the current study was to assess efficacy of EVs in an ACM murine model. Four-week-old homozygous knock-in mutant desmoglein-2 (Dsg2mt/mt) were randomized to receive weekly EVs or vehicle for 4 weeks. After 4 weeks, DSG2mt/mt mice receiving EVs showed improved biventricular function (left, P < 0.0001; right, P = 0.0037) and less left ventricular dilation (P < 0.0179). Electrocardiography revealed abbreviated QRS duration (P = 0.0003) and QTc interval (P = 0.0006) in EV-treated DSG2mt/mt mice. Further electrophysiology testing in the EV group showed decreased burden (P = 0.0042) and inducibility of ventricular arrhythmias (P = 0.0037). Optical mapping demonstrated accelerated repolarization (P = 0.0290) and faster conduction (P = 0.0274) in Dsg2mt/mt mice receiving EVs. DSG2mt/mt hearts exhibited reduced fibrosis, less cell death, and preserved connexin 43 expression after EV treatment. Hearts of Dsg2mt/mt mice expressed markedly increased levels of inflammatory cytokines that were, in part, attenuated by EV therapy. The pan-inflammatory transcription factor nuclear factor-κB (NF-κB), the inflammasome sensor NLRP3, and the macrophage marker CD68 were all reduced in EV-treated animals. Blocking EV hsa-miR-4488 in vitro and in vivo reactivates NF-κB and blunts the beneficial effects of EVs. Extracellular vesicle treatment improved cardiac function, reduced cardiac inflammation, and suppressed arrhythmogenesis in ACM. Further studies are needed prior to translating the present findings to human forms of this heterogenous disease.
2023-08-07 | Biological Modification of Arrhythmogenic Substrates by Cell-Free Therapeutics.
Ventricular arrhythmias (VAs) represent a major cause of sudden cardiac death and afflict patients with heart failure from both ischaemic and non-ischaemic origins, and inherited cardiomyopathies. Current VA management, including anti-arrhythmic medications, autonomic modulation, implantable cardioverter-defibrillator implantation, and catheter ablation, remains suboptimal. Catheter ablation may even cause significant cardiomyocyte loss. Cell-based therapies and exosome treatment have been proposed as promising strategies to lessen cardiomyocyte death, modulate immune reaction, and reduce myocardial scarring, and, therefore, are potentially beneficial in treating VAs. In this review, we summarise the current cornerstones of VA management. We also discuss recent advances and ongoing evidence regarding cell-based and exosome therapy, with special attention to VA treatment.
oligonucleotides
2024-08-31 | Role of miRNA-mRNA Interactome in Pathophysiology of Arrhythmogenic Cardiomyopathy.
Arrhythmogenic cardiomyopathy is an inherited entity characterized by irregular cell-cell adhesion, cardiomyocyte death and fibro-fatty replacement of ventricular myocytes, leading to malignant ventricular arrythmias, contractile dysfunction and sudden cardiac death. Pathogenic variants in genes that encode desmosome are the predominant cause of arrhythmogenic cardiomyopathy. Moreover, signalling pathways such as Wnt/ß-catenin and transforming growth factor-β have been involved in the disease progression. However, still little is known about the molecular pathophysiological mechanisms that underlie arrhythmogenic cardiomyopathy pathogenesis. We used mRNA and small RNA sequencing to analyse the transcriptome of health and arrhythmogenic cardiomyopathy of autopsied human hearts. Our results showed 697 differentially expressed genes and eight differentially expressed miRNAs. Functional enrichment revealed mitochondrial respiratory-related pathways, impaired response to oxidative stress, apoptotic signalling pathways and inflammatory response-related and extracellular matrix response pathways. Furthermore, analysis of the miRNA-mRNA interactome identified eleven negatively correlated miRNA-target pairs for arrhythmogenic cardiomyopathy. Our finding revealed novel arrhythmogenic cardiomyopathy-related miRNAs with important regulatory function in disease pathogenesis, highlighting their value as potential key targets for therapeutic approaches.
2023-03-20 | PITX2 induction leads to impaired cardiomyocyte function in arrhythmogenic cardiomyopathy.
Arrhythmogenic cardiomyopathy (ACM) is an inherited progressive disease characterized by electrophysiological and structural remodeling of the ventricles. However, the disease-causing molecular pathways, as a consequence of desmosomal mutations, are poorly understood. Here, we identified a novel missense mutation within desmoplakin in a patient clinically diagnosed with ACM. Using CRISPR-Cas9, we corrected this mutation in patient-derived human induced pluripotent stem cells (hiPSCs) and generated an independent knockin hiPSC line carrying the same mutation. Mutant cardiomyocytes displayed a decline in connexin 43, NaV1.5, and desmosomal proteins, which was accompanied by a prolonged action potential duration. Interestingly, paired-like homeodomain 2 (PITX2), a transcription factor that acts a repressor of connexin 43, NaV1.5, and desmoplakin, was induced in mutant cardiomyocytes. We validated these results in control cardiomyocytes in which PITX2 was either depleted or overexpressed. Importantly, knockdown of PITX2 in patient-derived cardiomyocytes is sufficient to restore the levels of desmoplakin, connexin 43, and NaV1.5.
2021-11-01 | Epicardial differentiation drives fibro-fatty remodeling in arrhythmogenic cardiomyopathy.
Arrhythmogenic cardiomyopathy (ACM) is an inherited disorder often caused by pathogenic variants in desmosomal genes and characterized by progressive fibrotic and fat tissue accumulation in the heart. The cellular origin and responsible molecular mechanisms of fibro-fatty deposits have been a matter of debate, due to limitations in animal models recapitulating this phenotype. Here, we used human-induced pluripotent stem cell (hiPSC)–derived cardiac cultures, single-cell RNA sequencing (scRNA-seq), and explanted human ACM hearts to study the epicardial contribution to fibro-fatty remodeling in ACM. hiPSC-epicardial cells generated from patients with ACM showed spontaneous fibro-fatty cellular differentiation that was absent in isogenic controls. This was further corroborated upon siRNA-mediated targeting of desmosomal genes in hiPSC-epicardial cells generated from healthy donors. scRNA-seq analysis identified the transcription factor TFAP2A (activating enhancer-binding protein 2 alpha) as a key trigger promoting this process. Gain- and loss-of-function studies on hiPSC-epicardial cells and primary adult epicardial-derived cells demonstrated that TFAP2A mediated epicardial differentiation through enhancing epithelial-to-mesenchymal transition (EMT). Furthermore, examination of explanted hearts from patients with ACM revealed epicardial activation and expression of TFAP2A in the subepicardial mesenchyme. These data suggest that TFAP2A-mediated epicardial EMT underlies fibro-fatty remodeling in ACM, a process amenable to therapeutic intervention.
2021-06-07 | Intracellular calcium current disorder and disease phenotype in OBSCN mutant iPSC-based cardiomyocytes in arrhythmogenic right ventricular cardiomyopathy.
Obscurin participates in the development of striated muscles and maintenance of the functional sarcoplasmic reticulum. However, the role of obscurin in arrhythmogenic right ventricular cardiomyopathy (ARVC) is not well understood. We aimed to study the novel obscurin mutations in the pathogenesis of ARVC and the underlying mechanisms. Methods: We generated induced pluripotent stem cells (iPSC) through retroviral reprogramming of peripheral blood mononuclear cells isolated from a 46-year-old female diagnosed with ARVC, carrying a mutation in OBSCN. The cells differentiated into functional iPSC-based cardiomyocytes (iPSC-CMs), whose phenotype was determined by transmission electron microscopy, electrophysiological description, immunofluorescence staining, and Oil Red O staining. Molecular characterization was performed by bioinformatic analyses, and identification by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. Results: ARVC-iPSC-CMs mutation in OBSCN showed significant accumulation of lipids, increased pleomorphism, irregular Z-bands, and increased L type calcium currents. Functional enrichment analysis identified pathways involved in focal adhesion and structure formation; the adipocytokines and PPAR signaling pathways were also activated in the ARVC group. Moreover, our results from ultra-high-resolution microscopy, qRT-PCR and Western blotting confirmed that the mutant OBSCN protein and its anchor protein, Ank1.5, showed structural disorder and decreased expression, but there was increased expression of junctional protein N-Cadherin. Further analysis revealed the gene expression of other desmosomal proteins in ARVC-iPSC-CMs was also decreased but some adipogenesis pathway-related proteins (PPARγ, C/EBPα, and FABP4) were increased. Conclusion: A novel frameshift mutation in OBSCN caused phenotypic alteration accompanied by disrupted localization and decreased expression of its anchoring protein Ank1.5. Furthermore, there was an accumulation of lipids with an increase in fatty fibrosis area and myocardial structural disorder, possibly leading to dysrhythmia in calcium channel-related myocardial contraction. These observations suggested the possibility of attenuating ARVC progression by therapeutic modulation of OBSCN expression.
2020-05-04 | A novel murine model for arrhythmogenic cardiomyopathy points to a pathogenic role of Wnt signalling and miRNA dysregulation.
Arrhythmogenic cardiomyopathy (AC) is one of the most common inherited cardiomyopathies, characterized by progressive fibro-fatty replacement in the myocardium. Clinically, AC manifests itself with ventricular arrhythmias, syncope, and sudden death and shows wide inter- and intra-familial variability. Among the causative genes identified so far, those encoding for the desmosomal proteins plakophilin-2 (PKP2), desmoplakin (DSP), and desmoglein-2 (DSG2) are the most commonly mutated. So far, little is known about the molecular mechanism(s) behind such a varied spectrum of phenotypes, although it has been shown that the causative mutations not only lead to structural abnormalities but also affect the miRNA profiling of cardiac tissue. Here, we aimed at studying the pathogenic effects of a nonsense mutation of the desmoglein-2 gene, both at the structural level and in terms of miRNA expression pattern. We generated transgenic mice with cardiomyocyte-specific overexpression of a FLAG-tagged human desmoglein-2 harbouring the Q558* nonsense mutation found in an AC patient. The hearts of these mice showed signs of fibrosis, decrease in desmosomal size and number, and reduction of the Wnt/β-catenin signalling. Genome-wide RNA-Seq performed in Tg-hQ hearts and non-transgenic hearts revealed that 24 miRNAs were dysregulated in transgenic animals. Further bioinformatic analyses for selected miRNAs suggested that miR-217-5p, miR-499-5p, and miR-708-5p might be involved in the pathogenesis of the disease. Down-regulation of the canonical Wnt/β-catenin signalling might be considered a common key event in the AC pathogenesis. We identified the miRNA signature in AC hearts, with miR-708-5p and miR-217-5p being the most up-regulated and miR-499-5p the most down-regulated miRNAs. All of them were predicted to be involved in the regulation of the Wnt/β-catenin pathway and might reveal the potential pathophysiology mechanisms of AC, as well as be useful as therapeutic targets for the disease.
other
2026-09-29 | Neurocardiac crosstalk in inherited cardiac arrhythmias and cardiomyopathy.
Inherited cardiac conditions are a leading cause of sudden cardiac death in young and otherwise healthy patients. They result from mutations in genes that encode proteins with various physiological functions. Despite knowledge of the underlying genetic basis, the disorders remain incompletely understood. There is significant interindividual variability in disease expression amongst patients, and incomplete penetrance amongst mutation carriers, indicating a more complex basis to these disorders. This review first discusses the well-established role of the autonomic nervous system (ANS) in acquired cardiac conditions, and subsequently focuses on several classically considered 'cardiac' conditions in which the ANS is known to play an important role: the inherited channelopathies catecholaminergic polymorphic ventricular tachycardia (CPVT), Brugada syndrome (BrS) and long QT syndrome type 3 (LQT3), as well as an inherited arrhythmogenic cardiomyopathy (ACM). Despite each condition being caused by different genetic mutations, they share a fundamental commonality in that cardiac-modulating neurons (e.g. those of the stellate and intracardiac ganglia) have recently been shown to be affected in addition to cardiomyocytes. Through closer examination of the pathophysiological contribution of a dysfunctional ANS to these conditions, novel avenues for both risk stratification and treatment design are likely to emerge.
2025-12-26 | Hot phase episodes in arrhythmogenic cardiomyopathy: More than just a desmoplakin issue?
Arrhythmogenic cardiomyopathy (ACM) is a genetically determined myocardial disease characterized by myocyte loss, fibro-fatty replacement, and electrical instability. In a subset of patients, episodes of chest pain with troponin release and electrocardiographic abnormalities occur in the absence of ischemic causes. These events, commonly referred to as "hot phases" (HP), often mimic acute myocarditis and raise important diagnostic and prognostic considerations. Among ACM-related genes, desmoplakin (DSP) variants are most frequently associated with HP, although episodes have also been observed in carriers of genes not classically associated with this presentation. Evidence suggests that HP presentation may vary across genotypes and ACM phenotypes, with DSP carriers more often exhibiting left sided or biventricular involvement. Growing data indicate that inflammation, autoimmunity, and innate immune activation play a central role in HP expression and ACM pathobiology, supported by findings of myocardial inflammatory infiltrates, circulating anti-desmosomal and anti-intercalated disc autoantibodies, and activation of NLRP3-inflammasome pathways. These mechanisms may contribute to disease progression and arrhythmic vulnerability. Therapeutic strategies remain empirical, but recent observations suggest that immunosuppressive therapy may modulate arrhythmic and heart-failure outcomes in DSP carriers. This review summarizes current knowledge on the clinical, genetic and immunologic features of HP in ACM, and discusses how these findings may refine the diagnostic approach and clinical interpretation of myocarditis-like presentations.
2025-12-23 | Maintenance of Energy Metabolism Is an Integral Part of Plakophilin-2 and Desmosome Functions.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial cardiac disease associated with ventricular arrhythmias and an increased risk of sudden cardiac death. Alterations in the desmosome gene plakophilin-2 (PKP2) lead to compromised contractility and electrical instability of cardiomyocytes. In this study, we utilized ARVC mouse and human induced pluripotent stem cell-derived cardiomyocyte models to confirm impaired energy metabolism that concorded with the human data. Our results supported an intrinsic cellular link between PKP2 and energy metabolism. TN-401-mediated PKP2 expression improved mitochondrial and glycolytic energetics and rescued cardiomyocyte functions that are dictated by mechanical and structural integrity of desmosome. Therefore, maintaining energy metabolism of cardiomyocytes is an integral part of PKP2 and desmosome functions, adding a new layer of understanding to ARVC disease mechanism.
2025-10-28 | Modelling arrhythmogenic cardiomyopathy fattyfibro pathology with PKP2-deficient epicardial cells derived from human iPSCs.
Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disease marked by progressive fattyfibro replacement of the ventricular myocardium, life-threatening arrhythmias, and sudden cardiac death. To dissect epicardial contributions to ACM pathogenesis, we generated iPSC lines from patients carrying plakophilin 2 (PKP2) 1849C > T or PKP2 2013delC mutations, their CRISPR/Cas9-corrected isogenic controls, and a PKP2 knockout line. Epicardial cells (hPSC-EPCs) differentiated from mutant and knockout backgrounds exhibit enhanced epithelial-to-mesenchymal transition characteristics, increased lipid accumulation, and a pronounced fibrotic phenotype. RNA-seq performed on ACM hPSC-EPCs reveals dysregulation of Wnt, interferon, and Rho GTPase signaling, including an upregulation of insulin growth factor 2 (IGF2) and a key adipogenic transcription factor, CEBPA. Subsequent treatment of control and PKP2KO hPSC-EPCs with recombinant IGF2 enhances CEBPA expression, suggesting that insulin growth factor signaling contributes to ACM fattyfibro remodeling.
2025-04-16 | Cardiac Magnetic Resonance Guidance for the Pathogenetic Definition of Cardiomyopathies.
Pathogenetics is the study of genetics in disease pathogenesis. Many abnormal gene alleles have been identified in cardiomyopathies, but their clinical utility remains limited. This review aims to examine the integration of cardiac MRI (CMR) with genetic data to enhance early detection, prognostication, and treatment strategies for cardiomyopathies. CMR is the gold standard imaging modality for cardiomyopathy evaluation, capable of detecting subtle structural and functional changes throughout the disease course. When applied to patients with genetic mutations, with or without phenotypic expression, CMR aids in early diagnosis and risk stratification. Cardiomyopathies can be categorized into at least seven clinical groups based on morphology, function, and genetic associations: (1) Dilated cardiomyopathy (DCM), (2) Hypertrophic cardiomyopathy (HCM), (3) Restrictive cardiomyopathy, including transthyretin amyloidosis (ATTR-CM), iron overload, and Anderson-Fabry disease, (4) Arrhythmogenic cardiomyopathy (ACM), (5) Non-dilated left ventricular cardiomyopathy (NDLVC), (6) Peripartum cardiomyopathy, and (7) Muscular dystrophy-related cardiomyopathy. We have described left ventricular noncompaction (LVNC) as a morphological trait rather than a distinct cardiomyopathy. Emerging CMR and genetic data suggest an inflammatory component in DCM and ACM, with potential therapeutic implications for immunotherapy. Advanced CMR techniques, such as quantitative perfusion, can distinguish cardiomyopathies from ischemic heart disease and detect early microvascular dysfunction, particularly in ATTR-CM and HCM. Late gadolinium enhancement (LGE) and parametric mapping (T1 and extracellular volume [ECV]) further enhance early diagnosis, prognostication and treatment response by assessing fibrosis and myocardial composition. The integration of CMR and genetic insights improves our understanding of cardiomyopathy pathogenesis, aiding in early diagnosis and prognostic assessment. Future research should leverage artificial intelligence (AI) to analyze genetic and radiomic CMR features, including perfusion data, to establish a comprehensive pathogenetic framework. This approach could refine disease classification, identify novel therapeutic targets, and advance precision medicine in cardiomyopathy management.
small molecules
2026-09-04 | Lipid Metabolism as a Therapeutic Target in Arrhythmogenic Cardiomyopathy: Emerging Therapeutic Implications of Lipid-Lowering Therapy.
Arrhythmogenic cardiomyopathy (ACM) is a hereditary myocardial disorder characterized by progressive replacement of ventricular myocardium with fibro-fatty tissue, leading to life-threatening ventricular arrhythmias and heart failure. Historically, management has focused on arrhythmia suppression and prevention of sudden cardiac death (SCD). However, recent advances in understanding disease mechanisms have redefined ACM as a structural-metabolic cardiomyopathy. Central to this evolving paradigm is the "adipogenic switch", driven by desmosomal dysfunction, impaired Wnt/β-catenin signaling, and activation of the peroxisome proliferator-activated receptor gamma (PPARγ) pathway. Emerging evidence highlights the critical role of metabolic dysregulation, specifically the oxidized low-density lipoprotein (oxLDL)/cluster of differentiation 36 (CD36)/PPARγ axis, in driving disease progression. Elevated oxLDL levels correlate with greater phenotypic severity, increased ventricular fat infiltration, and a higher arrhythmic risk. Translational models demonstrate that high-fat diets exacerbate the ACM phenotype, whereas lipid-lowering interventions, particularly statins, show potential to arrest fibro-fatty remodeling. In addition to the primary inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase associated with statins, these medications exert pleiotropic effects, including attenuation of systemic inflammation, stabilization of the intercalated disc via Rho GTPase modulation, and reduction of oxidative stress. Clinical data from non-ischemic dilated cardiomyopathy (NIDCM) suggest that lipophilic statins such as atorvastatin, may confer significant mortality and antiarrhythmic benefits by stabilizing the myocardial electrical substrate. The ongoing SEARCH trial (NCT06922994) represents a landmark effort to translate these insights into clinical practice. Using high-dose atorvastatin and sensitive primary endpoints, such as right ventricular free wall longitudinal strain, this study aimed to determine whether lipid-lowering therapy can function as a true disease-modifying intervention in ACM. The integration of lipid-lowering agents into the therapeutic armamentarium for ACM could enable a transition toward precision medicine, contingent upon successful clinical validation. If clinical trials confirm the efficacy of these agents in slowing myocardial substrate decay, this approach could redefine the management of ACM, including the use of targeted molecular strategies to preserve myocardial identity and electrical stability.
2026-07-08 | Genotype-Specific Electrophysiological Remodeling in PLN R14del Cardiomyopathy: Implications for Precision Antiarrhythmic Therapy.
Inherited PLN (phospholamban) R14del variants cause dilated cardiomyopathy with a high burden of malignant ventricular arrhythmias. However, the single-cell electrophysiological substrate underlying arrhythmogenicity is incompletely characterized, and it is unclear whether antiarrhythmic agents validated in wild-type (WT) or long QT models retain efficacy in this genotype. We sought to define the genotype-specific electrophysiological phenotype of PLN R14del cardiomyocytes and evaluate how modulation of the transient outward potassium current and late sodium current alters arrhythmic risk. Isogenic WT (HD.15S1) and CRISPR (clustered regularly interspaced short palindromic repeats)-edited PLN R14del human induced pluripotent stem cell-derived cardiomyocytes were studied using high-throughput optical action potential (AP) recordings. A deep learning framework classified AP morphology to quantify normal versus aberrant AP types, AP duration, and early afterdepolarization incidence at baseline and under graded concentrations of the transient outward potassium current activator NS-5806, the transient outward potassium current inhibitor acacetin, and the selective late sodium current blocker GS-967 (eleclazine). At baseline, PLN R14del human induced pluripotent stem cell-derived cardiomyocytes exhibited a subtle but significant arrhythmogenic phenotype, with a reduced proportion of normal APs, prolonged AP duration, and increased early afterdepolarizations compared with isogenic WT, consistent with impaired calcium handling and diminished repolarization reserve. In WT cells, NS-5806 produced a biphasic, dose-dependent response, transiently destabilizing and then restoring normal AP morphology; in PLN R14del cells, NS-5806 induced marked proarrhythmic remodeling and near-complete loss of normal APs at higher doses. GS-967 paradoxically exacerbated arrhythmic features in the mutant line, including AP duration prolongation and suppression of normal APs. Acacetin preserved stability in WT cells but failed to rescue normal AP morphology in PLN R14del cardiomyocytes. PLN R14del cardiomyopathy creates a distinct electrophysiological substrate that fundamentally alters antiarrhythmic drug responsiveness, such that agents beneficial in WT contexts may be ineffective or proarrhythmic in this genotype. Preclinical antiarrhythmic evaluation should incorporate genotype-specific, patient-derived human induced pluripotent stem cell models to enable precision medicine strategies in inherited cardiomyopathies.
2026-06-29 | TGF-β2 signaling promotes cardiac fibrosis in arrhythmogenic right ventricular cardiomyopathy mediated by DSC2 deficiency.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by progressive fibrofatty replacement of the right ventricular myocardium, ventricular arrhythmias, and an increased risk of sudden cardiac death. Pathogenic variants of desmosomal genes have been implicated in ARVC pathogenesis and may disrupt desmosomal protein function. However, whether and how desmosomal protein dysfunction directly activates cardiac fibroblasts to mediate fibrosis remains poorly understood. To address this, we combined genetic analysis with in vivo and cellular models to investigate the role of desmosomal dysfunction in cardiac fibrosis. The systematic genetic analysis revealed that desmosomal gene variants are predominant in ARVC, accounting for 67.4% of cases in cohort studies and 96.1% of pathogenic variants in ClinVar. We used desmocollin-2 (DSC2) knockout mice to recapitulate key features of ARVC, including right ventricular fibrosis, enlargement, and dysfunction. In vitro, DSC2 deficiency directly activates cardiac fibroblasts, resulting in increased cell proliferation, migration, and fibrosis marker expression. Further analysis identified transforming growth factor beta-2 (TGF-β2) as a critical signaling mediator in cardiac fibrosis of DSC2 deficiency-mediated ARVC. Mechanistically, DSC2 deficiency upregulated transcription factor 7 (TCF7) expression, promoting its binding to TGF-β2 promoter regions to enhance TGF-β2 transcription in cardiac fibroblasts. Pharmacological inhibition of TGF-β2 with pirfenidone (PFD) effectively attenuated cardiac fibrosis and improved right ventricular function in DSC2-deficient hearts. The results of the present study identified DSC2 deficiency-mediated TCF7-TGF-β2 signaling in cardiac fibroblasts, which contributed to ARVC development. Thus, targeting TGF-β2 signaling may be a promising therapeutic strategy for desmosome gene mutation-related ARVC.
2026-06-27 | Desmoglein-2 Deficiency Drives Mitochondrial Morphological Remodeling in Cardiomyocytes.
Pathogenic variants in desmoglein-2 (DSG2) are a major cause of arrhythmogenic cardiomyopathy (ACM), a disease plagued by ventricular arrhythmias, contractile dysfunction, myocardial inflammation, and fibrofatty remodeling. Additionally, increasing evidence implicates mitochondrial dysfunction in DSG2-associated disease. However, whether mitochondrial remodeling occurs uniformly across ventricles remains less well defined. Here, we utilized a homozygous Dsg2 mutant (Dsg2mut/mut) mouse to define chamber-specific mitochondrial remodeling in DSG2-linked ACM. Re-analysis of our previously generated cardiomyocyte snRNAseq dataset revealed broad downregulation of mitochondrial transcripts involved in fusion/fission dynamics, calcium handling, mitophagy, structural organization, and electron transport chain (ETC) assembly, findings that are consistent with impaired mitochondrial homeostasis and bioenergetic capacity. Ultrastructural analyses by transmission electron microscopy showed that Dsg2mut/mut hearts contained an increased number of mitochondria, which were smaller, irregularly shaped, and more disorganized than wildtype (WT) counterparts. Importantly, these alterations were chamber-dependent, with the right ventricle (RV) displaying more pronounced reductions in mitochondrial circularity and greater mitochxondrial abundance than the left ventricle (LV), indicating increased RV susceptibility. Together, these findings unveil mitochondrial remodeling as a feature of DSG2-deficiency and support a desmosomal-mitochondrial axis in ACM pathogenesis, further supporting mitochondrial pathways as candidate therapeutic targets.
2026-06-23 | Sacubitril/valsartan in paediatric cardiomyopathy: a retrospective evaluation of ventricular response and clinical outcomes.
Sacubitril/valsartan is widely used in adults with heart failure with reduced ejection fraction, but paediatric experience, especially across ventricular dysfunction phenotypes, remains limited. To evaluate the efficacy and tolerability of sacubitril/valsartan in children with cardiomyopathy and compare outcomes in patients with predominantly right or left ventricular dysfunction. This single-centre retrospective study included 33 patients aged 1 month to 18 years who received sacubitril/valsartan between October 2020 and October 2024. Diagnoses included arrhythmogenic right ventricular cardiomyopathy, left ventricular non-compaction, and dilated cardiomyopathy. Patients were stratified by predominant ventricular dysfunction. Echocardiographic parameters, N-terminal pro B-type natriuretic peptide, six-minute walk test, NYHA class, blood pressure, creatinine, and potassium were recorded at baseline and at 1, 3, and 6 months, and at final follow-up. Clinical outcomes included rehospitalisation, death, and heart transplantation or listing. The cohort included 21 male patients (63.6%), and the median age was 8.6 years. Arrhythmogenic right ventricular cardiomyopathy was present in 45.5%, left ventricular non-compaction in 15.2%, and dilated cardiomyopathy in 39.4%. Left ventricular ejection fraction >45% increased from 39.4% to 72.7%. Mean N-terminal pro B-type natriuretic peptide decreased from 6309 to 3137 pg/mL (p < 0.001). NYHA class improved or remained stable in 93.3% of patients, with greater improvement in left ventricular dysfunction. During a median 17.3-months follow-up, rehospitalisation occurred in 42.4%, and 5 patients died or underwent heart transplantation/listing. Hypotension occurred in 18.2% but was manageable. Sacubitril/valsartan was generally well tolerated and associated with improved ventricular function, biomarkers, and functional status in paediatric cardiomyopathy, particularly in left ventricular dysfunction.
gene therapies
2026-05-11 | Gene Therapy for Cardiomyopathy: Tools, Targets, and Trials.
Cardiomyopathy remains a leading cause of heart failure-related morbidity and mortality, driven by diverse genetic architectures that include monogenic variants, oligogenic interactions, and polygenic risk. Rapid advances in genomic medicine and vector engineering have positioned cardiac gene therapy as a transformative therapeutic approach. Adeno-associated virus-mediated gene replacement for hypertrophic, dilated, and arrhythmogenic cardiomyopathies has transitioned into early-phase clinical trials, with emerging data providing promising signals of myocardial transgene expression and improvements in circulating biomarkers such as NT-proBNP (N-terminal pro-B-type natriuretic peptide). Genome-editing platforms-including CRISPR-mediated base editing and prime editing-offer the potential for durable variant correction without introducing double-stranded breaks. Yet, major translational challenges remain, including strategies to bypass liver uptake to ensure high-efficiency transduction of cardiomyocytes, overcoming delivery constraints, including the cargo size of adeno-associated virus vectors, addressing toxicities, and establishing adequate immunosuppressive regimens. Novel strategies such as direct antegrade and retrograde coronary infusion, capsid engineering, split-intein dual-adeno-associated virus systems, miniaturization of CRISPR-related proteins, and nonviral nanoparticles are underway. As first-in-human cardiomyopathy gene therapy trials begin to define safety, dosing, and vector tropism in the failing human heart, the field is entering an inflection point where genomic diagnosis, molecular correction, and phenotype-guided delivery can converge into precision heart failure therapeutics. This review highlights current progress, emerging platforms, and scientific hurdles that must be overcome to realize a new era of potentially curative, mechanism-directed therapy for inherited and acquired cardiomyopathies.
2026-04-10 | Gene Editing Strategies (CRISPR) for Inherited Cardiomyopathies: Ethical, Technical and Clinical Review
Background: Inherited cardiomyopathies, such as hypertrophic, dilated and arrhythmogenic, are mediated by clearly defined genetic variants that are hard to combat using traditional therapy. Recent developments of gene-editing systems including CRISPRCas systems provide the opportunity to correct the causative mutations however, their translation elicits complicated ethical, technical and clinical issues. Objective: To overview the existing gene-editing options of inherited cardiomyopathies and assess their therapeutic potential, obstacles and available challenges of clinical use. Method: This was a review of preclinical research, initial therapeutic trials, genome-engineering system and bioethical models. It was emphasized on CRISPR-Cas9, base editing and prime-editing methods, as well as delivery methods such as AAV vectors and lipid nanoparticles. Moral considerations were done on the manipulation of germlines, off-target editing and long term consequences to society. Results: In animal and cellular models, gene editing demonstrated good possibilities in correcting pathogenic variants inMYH7, MYBPC3, LMNA and PKP2, and results were observed in improvement of myocardial structure and functioning. But there are still significant technical hurdles such as off-target effects, immune response to Cas proteins and limited efficacy of myocardial delivery. The ethical review pointed out the issues of germline edits, fair access and a long-term safety followup. Conclusion: Gene-editing technologies have a high potential of creating a new therapeutic alternative in inherited cardiomyopathies, considerable ethical, biological and translational challenges need to be overcome before clinical adoption. Additional streamline editing accuracy, delivery platform and regulatory authorities will be required to make them safe and responsible.
2026-04-04 | Adenovirus-associated viral vector-based gene-replacement therapy for the treatment of arrhythmogenic cardiomyopathy: A risk-benefit perspective in an evolving field.
Arrhythmogenic cardiomyopathy (ACM) is a primary disorder of the myocardium characterized by a high propension for ventricular arrhythmias (VAs) and sudden cardiac death (SCD). Several genes have been associated with the development of aggressive forms of ACM, the most common of which is the one encoding for plakophilin-2. Currently, no disease-modifying treatment for ACM exists and current therapeutic options are limited to implantable cardioverter defibrillator (ICD) for SCD prevention. In recent years, the use of adeno-associated viral vector (AAVV)-based gene-replacement therapies for the potential treatment of some ACM forms have been proposed with several technologies and related trials in the development pipeline. The main aim of this review is to highlight the state of current AAVV technologies, to summarize the prior experiences with their use in the field of cardiovascular medicine, and to specifically focus on the currently active trials with AAVV technologies in the field of ACM with a great focus on plakophilin-2 efforts. Side effects associated with AAVV administration, potential caveats associated with immunosuppression and realistic biological and clinical outcomes will be discussed in the review. We hope to provide data and perspective to clinicians to foster education in these novel technologies and to empower providers in their risk/benefit conversations with patients with ACM interested in pursuing them.
2026-02-28 | Fibroblast growth factor 21 prevents catecholaminergic arrhythmias in a mouse model of PKP2 arrhythmogenic cardiomyopathy.
Pathogenic variants in plakophilin-2 (PKP2) cause arrhythmogenic cardiomyopathy (ACM) with intracellular calcium dysregulation as a major component of its arrhythmia phenotype. Recent adeno-associated virus (AAV)-based PKP2 gene therapy has shown promising results in a few different PKP2-associated ACM models. Fibroblast growth factor 21 (FGF21) has multiple cardioprotective effects and has recently emerged as a promising therapeutic agent for cardiovascular disease. This study aimed to assess the efficacy and impact on calcium regulation of a novel AAV serotype 8 (AAV8)-based FGF21 gene therapy on adult cardiac-specific, tamoxifen-activated PKP2 knockout (PKP2-cKO) mice. Experiments were performed using a PKP2-cKO murine model. AAV8-FGF21 was delivered to adult mice by a single tail vein injection 7 days before tamoxifen-activated PKP2-cKO. Cardiac functions were monitored using echocardiography and electrocardiography. Intracellular calcium transients were investigated in acute isolated adult mouse cardiomyocytes, and calcium fluorescent signals were acquired using the IonOptix system. Loss of PKP2 expression caused cardiac mechanical dysfunction and proarrhythmic phenotype in adult mouse models. AAV-mediated delivery of FGF21 mitigated the progression of biventricular structural changes, decreased the occurrence of adrenergic arrhythmias, and rescued intracellular calcium imbalance in the setting of PKP2 haploinsufficiency. In contrast, acute in vitro FGF21 treatment for 1 hour had no effect on intracellular calcium transients. These beneficial effects of AAV8-FGF21 on the PKP2-ACM phenotype suggest a therapeutic landscape for various targeted cardiomyopathies.
2026-01-27 | Genetics of Sudden Cardiac Death.
Cardiomyopathies (DCM, HCM, and ACM) and primary arrhythmogenic disorders (BrS, LQTS, and CPVT) represent the most common causes of sudden cardiac death (SCD) in young individuals. Systematic genome-wide single-nucleotide polymorphism (SNP) analyses and genome-wide association studies (GWASs) have enabled the identification of numerous genetic variants associated with cardiovascular diseases. Body: Genetic testing for cardiomyopathies and inherited channelopathies primarily involves panel testing of genes with definitive and strong evidence of disease association; genes supported by moderate evidence may also be considered. Cardiomyocytes express a variety of proteins implicated in the pathogenesis of genetic cardiomyopathies, including sarcomeric, cytoskeletal, desmosomal, and nuclear envelope proteins. Inherited cardiac channelopathies result from mutations in genes encoding cellular components that influence calcium ion availability or affect membrane ion channels, including sodium, potassium, and calcium channels. Common variants associated with SCD are found in genes encoding cardiac ion channels (e.g., SCN5A, KCNQ1, and KCNH2), calmodulin (CALM2), sarcomeric proteins (MYH7, MYBPC3, TTN, and TNNI3), and desmosomal proteins (RyR2 and DES). This review demonstrates that specific genetic variants are significantly associated with an increased risk of SCD. The evidence underscores the importance of genetic screening and early intervention in individuals with a family history of SCD or other risk factors for inherited cardiac disorders predisposing to SCD. Future research should focus on gene-specific management strategies for familial cardiomyopathies and inherited channelopathies, with the goal of improving targeted genetic therapies and reducing the burden of sudden cardiac death.
cell therapies
2026-01-28 | Generation of a PKP2 heterozygous knockout pig model of arrhythmogenic cardiomyopathy.
Arrhythmogenic cardiomyopathy (ACM) confers elevated risk of ventricular arrhythmias and sudden cardiac death, yet limitations in early lesion sampling and model development continue to hinder mechanistic and translational research. Clinical, pathological, and mutational profiles were examined in 24 individuals with ACM harboring PKP2 variants. Among these, a patient carrying the c.1132C>T mutation exhibited the earliest onset and presented both structural cardiac abnormalities and major adverse cardiovascular events. To facilitate disease modeling, the c.1147C>T variant-a previously reported pathogenic substitution located proximal to position c.1132 in PKP2-was selected to enhance the feasibility of generating a porcine model. The BE3 gene editing system was used to induce C>T mutation. Two single guide RNAs targeting the PKP2 gene were designed (sgRNA1 for c.1132C>T and sgRNA2 for c.1147C>T), yielding editing efficiencies of 42.9% and 25.9%, respectively. SgRNA1 was used to generate PKP2 +/- porcine fetal fibroblasts. A total of 14 cloned piglets were produced, including 11 viable and three stillborn PKP2 +/- individuals. By 24 months of age, PKP2 +/- pigs developed premature ventricular contractions and right ventricular dilatation. Histological analysis revealed adipocyte infiltration within the right ventricular wall, and electron microscopy demonstrated reduced desmosomal length and electron density consistent with desmosomal dysfunction. Transcriptomic profiling showed high expression of genes associated with lipid catabolic processes. This study established the first PKP2 +/- porcine model of ACM using BE3-mediated base editing, providing a valuable platform for elucidating early pathogenic mechanisms and evaluating therapeutic interventions.
2025-11-03 | Cardiac sympathetic denervation for refractory ventricular arrhythmias in patients with inherited cardiomyopathies.
Cardiac sympathetic denervation (CSD) is a therapeutic option in patients with recurrent or refractory ventricular arrhythmia (VA). Successful outcomes have largely been established among patients with underlying ischemic cardiomyopathy, patients with nonischemic cardiomyopathy, and young patients diagnosed as having long-QT syndrome or catecholaminergic polymorphic ventricular tachycardia. Patients with inherited cardiomyopathies have a rare prevalence but experience VAs and sudden cardiac death. Herein, we studied the outcomes of CSD on patients with refractory VA and an inherited cardiomyopathy. Data from adult patients with VA referred for CSD were reviewed from 4 tertiary referral centers between 2010 and 2023. Patients with a minimum postoperative follow-up time of 12 months and an inherited cardiomyopathy were included: hypertrophic cardiomyopathy, arrhythmogenic cardiomyopathy, or dilated cardiomyopathy. 23 patients with an inherited cardiomyopathy underwent bilateral CSD: 7 patients with hypertrophic cardiomyopathy, 11 patients with arrhythmogenic cardiomyopathy, and 5 patients with dilated cardiomyopathy. The median (interquartile range) follow-up time was 34.5 months (23.1-46.5). The overall success rate of CSD was 48%. When comparing pre- and post-CSD periods, implantable cardioverter-defibrillator shocks decreased by 61% (P < .01). Transplant-free survival at 4 years was 76%. Most of the expected complications resolved upon follow-up. Bilateral CSD significantly reduced implantable cardioverter-defibrillator shocks in patients with inherited cardiomyopathies, demonstrating durable arrhythmia control and favorable long-term transplant-free survival across diverse genetic subtypes.
2025-08-26 | The blueprint of neurocardiac crosstalk in arrhythmic syndromes.
Inherited arrhythmogenic syndromes encompass a spectrum of genetic cardiac disorders unified by heightened vulnerability to sympathetic stimulation and risk of sudden cardiac death. Traditionally categorized as either functional (e.g., catecholaminergic polymorphic ventricular tachycardia, CPVT) or structural (e.g., arrhythmogenic cardiomyopathy, ACM), these syndromes are increasingly recognized to share a common reliance on neurocardiac signaling. In this review, we examine CPVT and ACM as representative extremes of the functional-structural continuum, highlighting how sympathetic activation acts not only as an acute arrhythmic trigger but also as a chronic driver of disease progression. We dissect the roles of β-adrenergic signaling, neuropeptide Y (NPY), and regional innervation patterns in shaping myocardial excitability, remodeling, and arrhythmogenesis. While CPVT exemplifies a trigger-dependent, Ca2+-driven arrhythmia in structurally normal hearts, ACM demonstrates a substrate-amplified phenotype involving maladaptive autonomic remodeling and neurogenic fibrofatty infiltration. We discuss the emerging relevance of neuromodulatory and peptidergic therapies-including β-blockade, left cardiac sympathetic denervation, and NPY antagonism-and propose an integrated framework for arrhythmia classification and management based on autonomic mechanisms. By reframing inherited arrhythmias as disorders of integrated neural and myocardial physiology, we highlight new opportunities for mechanistic insight, biomarker development, patient stratification, and translational therapy.
2024-02-23 | Extracellular vesicles from immortalized cardiosphere-derived cells attenuate arrhythmogenic cardiomyopathy in desmoglein-2 mutant mice.
Arrhythmogenic cardiomyopathy (ACM) is characterized by progressive loss of cardiomyocytes, and fibrofatty tissue replacement. Extracellular vesicles (EVs) secreted by cardiosphere-derived cells, immortalized, and engineered to express high levels of β-catenin, exert anti-inflammatory, and anti-fibrotic effects. The aim of the current study was to assess efficacy of EVs in an ACM murine model. Four-week-old homozygous knock-in mutant desmoglein-2 (Dsg2mt/mt) were randomized to receive weekly EVs or vehicle for 4 weeks. After 4 weeks, DSG2mt/mt mice receiving EVs showed improved biventricular function (left, P < 0.0001; right, P = 0.0037) and less left ventricular dilation (P < 0.0179). Electrocardiography revealed abbreviated QRS duration (P = 0.0003) and QTc interval (P = 0.0006) in EV-treated DSG2mt/mt mice. Further electrophysiology testing in the EV group showed decreased burden (P = 0.0042) and inducibility of ventricular arrhythmias (P = 0.0037). Optical mapping demonstrated accelerated repolarization (P = 0.0290) and faster conduction (P = 0.0274) in Dsg2mt/mt mice receiving EVs. DSG2mt/mt hearts exhibited reduced fibrosis, less cell death, and preserved connexin 43 expression after EV treatment. Hearts of Dsg2mt/mt mice expressed markedly increased levels of inflammatory cytokines that were, in part, attenuated by EV therapy. The pan-inflammatory transcription factor nuclear factor-κB (NF-κB), the inflammasome sensor NLRP3, and the macrophage marker CD68 were all reduced in EV-treated animals. Blocking EV hsa-miR-4488 in vitro and in vivo reactivates NF-κB and blunts the beneficial effects of EVs. Extracellular vesicle treatment improved cardiac function, reduced cardiac inflammation, and suppressed arrhythmogenesis in ACM. Further studies are needed prior to translating the present findings to human forms of this heterogenous disease.
2023-08-07 | Biological Modification of Arrhythmogenic Substrates by Cell-Free Therapeutics.
Ventricular arrhythmias (VAs) represent a major cause of sudden cardiac death and afflict patients with heart failure from both ischaemic and non-ischaemic origins, and inherited cardiomyopathies. Current VA management, including anti-arrhythmic medications, autonomic modulation, implantable cardioverter-defibrillator implantation, and catheter ablation, remains suboptimal. Catheter ablation may even cause significant cardiomyocyte loss. Cell-based therapies and exosome treatment have been proposed as promising strategies to lessen cardiomyocyte death, modulate immune reaction, and reduce myocardial scarring, and, therefore, are potentially beneficial in treating VAs. In this review, we summarise the current cornerstones of VA management. We also discuss recent advances and ongoing evidence regarding cell-based and exosome therapy, with special attention to VA treatment.
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2024-08-31 | Role of miRNA-mRNA Interactome in Pathophysiology of Arrhythmogenic Cardiomyopathy.
Arrhythmogenic cardiomyopathy is an inherited entity characterized by irregular cell-cell adhesion, cardiomyocyte death and fibro-fatty replacement of ventricular myocytes, leading to malignant ventricular arrythmias, contractile dysfunction and sudden cardiac death. Pathogenic variants in genes that encode desmosome are the predominant cause of arrhythmogenic cardiomyopathy. Moreover, signalling pathways such as Wnt/ß-catenin and transforming growth factor-β have been involved in the disease progression. However, still little is known about the molecular pathophysiological mechanisms that underlie arrhythmogenic cardiomyopathy pathogenesis. We used mRNA and small RNA sequencing to analyse the transcriptome of health and arrhythmogenic cardiomyopathy of autopsied human hearts. Our results showed 697 differentially expressed genes and eight differentially expressed miRNAs. Functional enrichment revealed mitochondrial respiratory-related pathways, impaired response to oxidative stress, apoptotic signalling pathways and inflammatory response-related and extracellular matrix response pathways. Furthermore, analysis of the miRNA-mRNA interactome identified eleven negatively correlated miRNA-target pairs for arrhythmogenic cardiomyopathy. Our finding revealed novel arrhythmogenic cardiomyopathy-related miRNAs with important regulatory function in disease pathogenesis, highlighting their value as potential key targets for therapeutic approaches.
2023-03-20 | PITX2 induction leads to impaired cardiomyocyte function in arrhythmogenic cardiomyopathy.
Arrhythmogenic cardiomyopathy (ACM) is an inherited progressive disease characterized by electrophysiological and structural remodeling of the ventricles. However, the disease-causing molecular pathways, as a consequence of desmosomal mutations, are poorly understood. Here, we identified a novel missense mutation within desmoplakin in a patient clinically diagnosed with ACM. Using CRISPR-Cas9, we corrected this mutation in patient-derived human induced pluripotent stem cells (hiPSCs) and generated an independent knockin hiPSC line carrying the same mutation. Mutant cardiomyocytes displayed a decline in connexin 43, NaV1.5, and desmosomal proteins, which was accompanied by a prolonged action potential duration. Interestingly, paired-like homeodomain 2 (PITX2), a transcription factor that acts a repressor of connexin 43, NaV1.5, and desmoplakin, was induced in mutant cardiomyocytes. We validated these results in control cardiomyocytes in which PITX2 was either depleted or overexpressed. Importantly, knockdown of PITX2 in patient-derived cardiomyocytes is sufficient to restore the levels of desmoplakin, connexin 43, and NaV1.5.
2021-11-01 | Epicardial differentiation drives fibro-fatty remodeling in arrhythmogenic cardiomyopathy.
Arrhythmogenic cardiomyopathy (ACM) is an inherited disorder often caused by pathogenic variants in desmosomal genes and characterized by progressive fibrotic and fat tissue accumulation in the heart. The cellular origin and responsible molecular mechanisms of fibro-fatty deposits have been a matter of debate, due to limitations in animal models recapitulating this phenotype. Here, we used human-induced pluripotent stem cell (hiPSC)–derived cardiac cultures, single-cell RNA sequencing (scRNA-seq), and explanted human ACM hearts to study the epicardial contribution to fibro-fatty remodeling in ACM. hiPSC-epicardial cells generated from patients with ACM showed spontaneous fibro-fatty cellular differentiation that was absent in isogenic controls. This was further corroborated upon siRNA-mediated targeting of desmosomal genes in hiPSC-epicardial cells generated from healthy donors. scRNA-seq analysis identified the transcription factor TFAP2A (activating enhancer-binding protein 2 alpha) as a key trigger promoting this process. Gain- and loss-of-function studies on hiPSC-epicardial cells and primary adult epicardial-derived cells demonstrated that TFAP2A mediated epicardial differentiation through enhancing epithelial-to-mesenchymal transition (EMT). Furthermore, examination of explanted hearts from patients with ACM revealed epicardial activation and expression of TFAP2A in the subepicardial mesenchyme. These data suggest that TFAP2A-mediated epicardial EMT underlies fibro-fatty remodeling in ACM, a process amenable to therapeutic intervention.
2021-06-07 | Intracellular calcium current disorder and disease phenotype in OBSCN mutant iPSC-based cardiomyocytes in arrhythmogenic right ventricular cardiomyopathy.
Obscurin participates in the development of striated muscles and maintenance of the functional sarcoplasmic reticulum. However, the role of obscurin in arrhythmogenic right ventricular cardiomyopathy (ARVC) is not well understood. We aimed to study the novel obscurin mutations in the pathogenesis of ARVC and the underlying mechanisms. Methods: We generated induced pluripotent stem cells (iPSC) through retroviral reprogramming of peripheral blood mononuclear cells isolated from a 46-year-old female diagnosed with ARVC, carrying a mutation in OBSCN. The cells differentiated into functional iPSC-based cardiomyocytes (iPSC-CMs), whose phenotype was determined by transmission electron microscopy, electrophysiological description, immunofluorescence staining, and Oil Red O staining. Molecular characterization was performed by bioinformatic analyses, and identification by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. Results: ARVC-iPSC-CMs mutation in OBSCN showed significant accumulation of lipids, increased pleomorphism, irregular Z-bands, and increased L type calcium currents. Functional enrichment analysis identified pathways involved in focal adhesion and structure formation; the adipocytokines and PPAR signaling pathways were also activated in the ARVC group. Moreover, our results from ultra-high-resolution microscopy, qRT-PCR and Western blotting confirmed that the mutant OBSCN protein and its anchor protein, Ank1.5, showed structural disorder and decreased expression, but there was increased expression of junctional protein N-Cadherin. Further analysis revealed the gene expression of other desmosomal proteins in ARVC-iPSC-CMs was also decreased but some adipogenesis pathway-related proteins (PPARγ, C/EBPα, and FABP4) were increased. Conclusion: A novel frameshift mutation in OBSCN caused phenotypic alteration accompanied by disrupted localization and decreased expression of its anchoring protein Ank1.5. Furthermore, there was an accumulation of lipids with an increase in fatty fibrosis area and myocardial structural disorder, possibly leading to dysrhythmia in calcium channel-related myocardial contraction. These observations suggested the possibility of attenuating ARVC progression by therapeutic modulation of OBSCN expression.
2020-05-04 | A novel murine model for arrhythmogenic cardiomyopathy points to a pathogenic role of Wnt signalling and miRNA dysregulation.
Arrhythmogenic cardiomyopathy (AC) is one of the most common inherited cardiomyopathies, characterized by progressive fibro-fatty replacement in the myocardium. Clinically, AC manifests itself with ventricular arrhythmias, syncope, and sudden death and shows wide inter- and intra-familial variability. Among the causative genes identified so far, those encoding for the desmosomal proteins plakophilin-2 (PKP2), desmoplakin (DSP), and desmoglein-2 (DSG2) are the most commonly mutated. So far, little is known about the molecular mechanism(s) behind such a varied spectrum of phenotypes, although it has been shown that the causative mutations not only lead to structural abnormalities but also affect the miRNA profiling of cardiac tissue. Here, we aimed at studying the pathogenic effects of a nonsense mutation of the desmoglein-2 gene, both at the structural level and in terms of miRNA expression pattern. We generated transgenic mice with cardiomyocyte-specific overexpression of a FLAG-tagged human desmoglein-2 harbouring the Q558* nonsense mutation found in an AC patient. The hearts of these mice showed signs of fibrosis, decrease in desmosomal size and number, and reduction of the Wnt/β-catenin signalling. Genome-wide RNA-Seq performed in Tg-hQ hearts and non-transgenic hearts revealed that 24 miRNAs were dysregulated in transgenic animals. Further bioinformatic analyses for selected miRNAs suggested that miR-217-5p, miR-499-5p, and miR-708-5p might be involved in the pathogenesis of the disease. Down-regulation of the canonical Wnt/β-catenin signalling might be considered a common key event in the AC pathogenesis. We identified the miRNA signature in AC hearts, with miR-708-5p and miR-217-5p being the most up-regulated and miR-499-5p the most down-regulated miRNAs. All of them were predicted to be involved in the regulation of the Wnt/β-catenin pathway and might reveal the potential pathophysiology mechanisms of AC, as well as be useful as therapeutic targets for the disease.
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2026-09-29 | Neurocardiac crosstalk in inherited cardiac arrhythmias and cardiomyopathy.
Inherited cardiac conditions are a leading cause of sudden cardiac death in young and otherwise healthy patients. They result from mutations in genes that encode proteins with various physiological functions. Despite knowledge of the underlying genetic basis, the disorders remain incompletely understood. There is significant interindividual variability in disease expression amongst patients, and incomplete penetrance amongst mutation carriers, indicating a more complex basis to these disorders. This review first discusses the well-established role of the autonomic nervous system (ANS) in acquired cardiac conditions, and subsequently focuses on several classically considered 'cardiac' conditions in which the ANS is known to play an important role: the inherited channelopathies catecholaminergic polymorphic ventricular tachycardia (CPVT), Brugada syndrome (BrS) and long QT syndrome type 3 (LQT3), as well as an inherited arrhythmogenic cardiomyopathy (ACM). Despite each condition being caused by different genetic mutations, they share a fundamental commonality in that cardiac-modulating neurons (e.g. those of the stellate and intracardiac ganglia) have recently been shown to be affected in addition to cardiomyocytes. Through closer examination of the pathophysiological contribution of a dysfunctional ANS to these conditions, novel avenues for both risk stratification and treatment design are likely to emerge.
2025-12-26 | Hot phase episodes in arrhythmogenic cardiomyopathy: More than just a desmoplakin issue?
Arrhythmogenic cardiomyopathy (ACM) is a genetically determined myocardial disease characterized by myocyte loss, fibro-fatty replacement, and electrical instability. In a subset of patients, episodes of chest pain with troponin release and electrocardiographic abnormalities occur in the absence of ischemic causes. These events, commonly referred to as "hot phases" (HP), often mimic acute myocarditis and raise important diagnostic and prognostic considerations. Among ACM-related genes, desmoplakin (DSP) variants are most frequently associated with HP, although episodes have also been observed in carriers of genes not classically associated with this presentation. Evidence suggests that HP presentation may vary across genotypes and ACM phenotypes, with DSP carriers more often exhibiting left sided or biventricular involvement. Growing data indicate that inflammation, autoimmunity, and innate immune activation play a central role in HP expression and ACM pathobiology, supported by findings of myocardial inflammatory infiltrates, circulating anti-desmosomal and anti-intercalated disc autoantibodies, and activation of NLRP3-inflammasome pathways. These mechanisms may contribute to disease progression and arrhythmic vulnerability. Therapeutic strategies remain empirical, but recent observations suggest that immunosuppressive therapy may modulate arrhythmic and heart-failure outcomes in DSP carriers. This review summarizes current knowledge on the clinical, genetic and immunologic features of HP in ACM, and discusses how these findings may refine the diagnostic approach and clinical interpretation of myocarditis-like presentations.
2025-12-23 | Maintenance of Energy Metabolism Is an Integral Part of Plakophilin-2 and Desmosome Functions.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial cardiac disease associated with ventricular arrhythmias and an increased risk of sudden cardiac death. Alterations in the desmosome gene plakophilin-2 (PKP2) lead to compromised contractility and electrical instability of cardiomyocytes. In this study, we utilized ARVC mouse and human induced pluripotent stem cell-derived cardiomyocyte models to confirm impaired energy metabolism that concorded with the human data. Our results supported an intrinsic cellular link between PKP2 and energy metabolism. TN-401-mediated PKP2 expression improved mitochondrial and glycolytic energetics and rescued cardiomyocyte functions that are dictated by mechanical and structural integrity of desmosome. Therefore, maintaining energy metabolism of cardiomyocytes is an integral part of PKP2 and desmosome functions, adding a new layer of understanding to ARVC disease mechanism.
2025-10-28 | Modelling arrhythmogenic cardiomyopathy fattyfibro pathology with PKP2-deficient epicardial cells derived from human iPSCs.
Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disease marked by progressive fattyfibro replacement of the ventricular myocardium, life-threatening arrhythmias, and sudden cardiac death. To dissect epicardial contributions to ACM pathogenesis, we generated iPSC lines from patients carrying plakophilin 2 (PKP2) 1849C > T or PKP2 2013delC mutations, their CRISPR/Cas9-corrected isogenic controls, and a PKP2 knockout line. Epicardial cells (hPSC-EPCs) differentiated from mutant and knockout backgrounds exhibit enhanced epithelial-to-mesenchymal transition characteristics, increased lipid accumulation, and a pronounced fibrotic phenotype. RNA-seq performed on ACM hPSC-EPCs reveals dysregulation of Wnt, interferon, and Rho GTPase signaling, including an upregulation of insulin growth factor 2 (IGF2) and a key adipogenic transcription factor, CEBPA. Subsequent treatment of control and PKP2KO hPSC-EPCs with recombinant IGF2 enhances CEBPA expression, suggesting that insulin growth factor signaling contributes to ACM fattyfibro remodeling.
2025-04-16 | Cardiac Magnetic Resonance Guidance for the Pathogenetic Definition of Cardiomyopathies.
Pathogenetics is the study of genetics in disease pathogenesis. Many abnormal gene alleles have been identified in cardiomyopathies, but their clinical utility remains limited. This review aims to examine the integration of cardiac MRI (CMR) with genetic data to enhance early detection, prognostication, and treatment strategies for cardiomyopathies. CMR is the gold standard imaging modality for cardiomyopathy evaluation, capable of detecting subtle structural and functional changes throughout the disease course. When applied to patients with genetic mutations, with or without phenotypic expression, CMR aids in early diagnosis and risk stratification. Cardiomyopathies can be categorized into at least seven clinical groups based on morphology, function, and genetic associations: (1) Dilated cardiomyopathy (DCM), (2) Hypertrophic cardiomyopathy (HCM), (3) Restrictive cardiomyopathy, including transthyretin amyloidosis (ATTR-CM), iron overload, and Anderson-Fabry disease, (4) Arrhythmogenic cardiomyopathy (ACM), (5) Non-dilated left ventricular cardiomyopathy (NDLVC), (6) Peripartum cardiomyopathy, and (7) Muscular dystrophy-related cardiomyopathy. We have described left ventricular noncompaction (LVNC) as a morphological trait rather than a distinct cardiomyopathy. Emerging CMR and genetic data suggest an inflammatory component in DCM and ACM, with potential therapeutic implications for immunotherapy. Advanced CMR techniques, such as quantitative perfusion, can distinguish cardiomyopathies from ischemic heart disease and detect early microvascular dysfunction, particularly in ATTR-CM and HCM. Late gadolinium enhancement (LGE) and parametric mapping (T1 and extracellular volume [ECV]) further enhance early diagnosis, prognostication and treatment response by assessing fibrosis and myocardial composition. The integration of CMR and genetic insights improves our understanding of cardiomyopathy pathogenesis, aiding in early diagnosis and prognostic assessment. Future research should leverage artificial intelligence (AI) to analyze genetic and radiomic CMR features, including perfusion data, to establish a comprehensive pathogenetic framework. This approach could refine disease classification, identify novel therapeutic targets, and advance precision medicine in cardiomyopathy management.
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Drug Discovery Landscape
5 orphan drug designations for Inherited arrhythmogenic cardiomyopathy.
5 orphan drug designations for Inherited arrhythmogenic cardiomyopathy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Small interfering RNA against the human PLN gene, conjugated to a bicyclic peptide, sodium salt | RNAs | EMA | AstraZeneca AB | |
Atibuclimab | antibodies | FDA | Implicit Bioscience Ltd. | |
Adeno-associated virus vector serotype 9 containing the PKP2 gene | gene therapies | EMA | Yes Pharmaceutical Development Services GmbH | |
Adeno-associated virus serotype rh.74 vector containing the human Plakophilin-2a transgene (AAVrh.74-PKP2a) | gene therapies | FDA | Rocket Pharmaceuticals, Inc. | |
A native AAV9 capsid with a genomic cassette containing a cardiomyocyte-specific promoter and the wild-type human PKP2 gene | gene therapies | FDA | Tenaya Therapeutics |
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